Optimization of dipeptide-linked benzimidazole topoisomerase 1 poisons

二肽连接苯并咪唑拓扑异构酶1毒物的优化

基本信息

  • 批准号:
    7665607
  • 负责人:
  • 金额:
    $ 26.1万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-09-18 至 2011-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Derivatives of camptothecin (CPT) that inhibit Topoisomerase I (Top1) activity have demonstrated clinical utility in the treatment of various cancers. However, limitations in CPT pharmaceutical properties have driven the search for new CPT-like poisons that target the Top1 protein-DNA cleavage complex. We hypothesized that bifunctional agents that simultaneously bind to the DNA minor groove and the nose-cone region of the Top1 protein would be effective poisons with pharmaceutical properties that are superior to the CPT congeners. Such compounds also should be effective against tumors that are otherwise resistant to the CPT structural class of poisons and should generally exhibit reduced toxicity compared to the CPT- class of agents such as topotecan. Structural insights from Top1-DNA crystal structures were used to design a small library of N-acetyl dipeptides linked to Hoechst 33258, a DNA minor groove binder. Screening of the library against a in vitro assays and subsequent library deconvolution afforded a high affinity (EC50 ~ 50 nM) agent, LL217, that also caused growth arrest of several tumor cell lines. Subsequent replacement of the Hoechst with a phenyl- substituted monobenzimidazole provided the agent MB1 that exhibits tumor cell line killing activity similar to LL217 but with substantially reduced off-target effects. Biochemical assays performed with LL217 and MB1 demonstrate that the primary modality of action in tumor cell lines is cell cycle arrest due to inhibition of Top1 activity. Our long-term goal is to translate MB1 into a clinically efficacious drug. Our immediate goal is to produce a refined lead compound with sufficient tissue culture and murine xenograft data to support further development. The immediate goals will be achieved via four specific aims: (1) the structure of MB1 will be slightly modified to facilitate solution phase syntheses, (2) the in vitro and cellular activities of the MB1 derivatives will be assayed and compared to topotecan, (3) the potential therapeutic efficacy of MB1 will be evaluated in murine xenograft tumor models as compared to topotecan, and (4) the pharmaceutical properties of MB1 and topotecan will be evaluated. PUBLIC HEALTH RELEVANCE: Cancer has recently surpassed cardiovascular disease as a major cause of morbidity and mortality in the United States. Although new classes of chemotherapeutic agents are needed, it is also desirable to develop agents with improved pharmaceutical properties that target clinically validated targets. The camptothecin class of agents used in the clinic specifically target the Topoisomerase 1 enzyme. However, their poor solubilities and stabilities require the use of large doses, which increases the chances for adverse effects to the patient. The agents described here also target Topoisomerase 1, but they are expected to be more bioavailable and, thus, offer an improvement to the camptothecin class of agents. Because these agents are also structurally distinct, it is expected that they will be clinically efficacious against cancers that have developed resistance to the camptothecins.
描述(由申请人提供):抑制拓扑异构酶I(Top1)活性的喜树碱(CPT)衍生物已证明在治疗各种癌症中具有临床效用。然而,CPT药物特性的局限性已经推动了对靶向Top1蛋白-DNA切割复合物的新CPT样毒物的研究。我们假设,同时结合到DNA小沟和Top1蛋白的鼻锥区域的双功能试剂将是具有上级CPT同类物的药物特性的有效毒药。这样的化合物还应该有效对抗否则对CPT结构类别的毒物具有抗性的肿瘤,并且与CPT类别的药剂如托泊替康相比,通常应该表现出降低的毒性。从Top1-DNA晶体结构的结构见解被用来设计连接到Hoechst 33258(DNA小沟结合剂)的N-乙酰基二肽的小型文库。针对体外测定筛选文库和随后的文库去卷积提供了高亲和力(EC 50 ~ 50 nM)试剂LL 217,其也引起几种肿瘤细胞系的生长停滞。随后用苯基取代的单苯并咪唑代替Hoechst提供了表现出与LL 217相似的肿瘤细胞系杀伤活性但具有显著降低的脱靶效应的试剂MBl。用LL 217和MB 1进行的生化测定证明,在肿瘤细胞系中的主要作用方式是由于抑制Top1活性而导致的细胞周期停滞。我们的长期目标是将MB 1转化为临床有效的药物。我们的近期目标是生产一种精制的先导化合物,并提供足够的组织培养和小鼠异种移植数据来支持进一步的开发。近期目标将通过四个具体目标实现:(1)将对MB 1的结构进行轻微修饰以促进溶液相合成,(2)将测定MB 1衍生物的体外和细胞活性并与托泊替康进行比较,(3)将在鼠异种移植肿瘤模型中评价MB 1与托泊替康相比的潜在治疗功效,和(4)评价MB 1和拓扑替康的药物性质。 公共卫生相关性:癌症最近已超过心血管疾病,成为美国发病率和死亡率的主要原因。尽管需要新类别的化学治疗剂,但还期望开发具有改进的药物性质的药剂,其靶向临床验证的靶标。临床使用的喜树碱类药物特异性靶向拓扑异构酶1。然而,它们的溶解度和稳定性差,需要使用大剂量,这增加了对患者产生不良反应的机会。本文所述的药剂也靶向拓扑异构酶1,但预期它们具有更高的生物利用度,因此提供了对喜树碱类药剂的改进。因为这些药剂在结构上也是不同的,所以预期它们将在临床上有效地对抗已经对喜树碱产生耐药性的癌症。

项目成果

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Craig Cano Beeson其他文献

Craig Cano Beeson的其他文献

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{{ truncateString('Craig Cano Beeson', 18)}}的其他基金

Development of a lasmiditan analogue for treatment of acute kidney injury
开发用于治疗急性肾损伤的 lasmiditan 类似物
  • 批准号:
    8781967
  • 财政年份:
    2014
  • 资助金额:
    $ 26.1万
  • 项目类别:
High Throughput Extracellular Flux Analyzer
高通量细胞外通量分析仪
  • 批准号:
    8052392
  • 财政年份:
    2011
  • 资助金额:
    $ 26.1万
  • 项目类别:
Inducers of Mitochondrial Biogenesis
线粒体生物发生诱导剂
  • 批准号:
    8200080
  • 财政年份:
    2011
  • 资助金额:
    $ 26.1万
  • 项目类别:
Bioenergetics Core
生物能核心
  • 批准号:
    10005395
  • 财政年份:
    2011
  • 资助金额:
    $ 26.1万
  • 项目类别:
High Throughput Mitochondrial Nephrotoxicant Assay
高通量线粒体肾毒测定
  • 批准号:
    8253245
  • 财政年份:
    2010
  • 资助金额:
    $ 26.1万
  • 项目类别:
High Throughput Mitochondrial Nephrotoxicant Assay
高通量线粒体肾毒测定
  • 批准号:
    8001529
  • 财政年份:
    2010
  • 资助金额:
    $ 26.1万
  • 项目类别:
High Throughput Mitochondrial Nephrotoxicant Assay
高通量线粒体肾毒测定
  • 批准号:
    8334035
  • 财政年份:
    2010
  • 资助金额:
    $ 26.1万
  • 项目类别:
BINDING INTERACTIONS WITHIN PEPTIDE-MHC COMPLEXES
肽-MHC 复合物内的结合相互作用
  • 批准号:
    6386567
  • 财政年份:
    2000
  • 资助金额:
    $ 26.1万
  • 项目类别:
BINDING INTERACTIONS WITHIN PEPTIDE-MHC COMPLEXES
肽-MHC 复合物内的结合相互作用
  • 批准号:
    6127991
  • 财政年份:
    2000
  • 资助金额:
    $ 26.1万
  • 项目类别:
BINDING INTERACTIONS WITHIN PEPTIDE-MHC COMPLEXES
肽-MHC 复合物内的结合相互作用
  • 批准号:
    6690625
  • 财政年份:
    2000
  • 资助金额:
    $ 26.1万
  • 项目类别:

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